Cystic fibrosis (CF) is an inherited multi-system disorder that is characterized by an abnormality in exocrine gland function. More specifically, CF is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. The mutations in the CFTR gene result in an abnormal potential difference across CF epithelia. The abnormality is due to a reduced cellular apical Cl.sup.- conductance. Consequently, chloride and sodium transport across mucous membranes is abnormal. This abnormality is apparently responsible for pathophysiological changes in the respiratory system. Nearly all patients suffering from the disease develop chronic progressive disease of the respiratory system. Also, in the majority of cases, pancreatic dysfunction occurs, and hepatobiliary and genitourinary diseases are also frequent. The incidence of the disease among white Americans is between 1/1600 and 1/2000 live births. Among Afro-Americans, the incidence is much reduced--about 1/17,000 live births. Although survival of cystic fibrosis patients has improved in recent years, the median survival is still only about 20 years despite intensive supportive and prophylactic treatment.
Present efforts to combat the disease have focused on drugs that are capable of either activating the mutant CFTR gene product or causing additional secretion of Cl.sup.- from affected cells, as well as gene therapy, wherein the anion conductance deficit is repaired by the introduction of a recombinant wild-type CFTR gene, i.e., a CFTR gene that lacks a mutation that results in the abnormality.
Encouraging clinical results have been reported recently for the use of aerosols containing either amiloride (Knowles et al., N. Engl. J. Med. 322: 1189-1194. 1990.) or a mixture of ATP and UTP (Knowles et al., N. Engl. J. Med. 325: 533-538. 1991.), which slow the accumulation of Cl.sup.- in the epithelium of the trachea.
Other drugs that are purportedly useful in the treatment of CF have been described. For example, U.S. Pat. No. 4,866,072 describes the use of 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano(3,2-g)quinoline2,8-dicar boxylic acid or a pharmaceutically acceptable derivative thereof in the treatment of CF. U.S. Pat. No. 4,548,818 describes the use of a 3-alkylxanthine to treat chronic obstructive pulmonary disease (COPD). U.S. Pat. No. 5,032,593 describes the use of a 1,3-alkyl substituted 8-phenylxanthine or a pharmaceutically acceptable salt thereof in the treatment of bronchoconstriction. U.S. Pat. No. 5,096,916 describes the use of an imidazoline .alpha.-adrenergic blocking agent and vasodilator, such as tolazoline, in the treatment of COPD, including cystic fibrosis, chronic bronchitis and emphysema, or COPD in association with asthma.
Historically, theophylline has been administered to asthmatic and CF patients to enhance lung function. The mechanism of theophylline has been shown to involve both the inhibition of phosphodiesterase and the antagonism of adenosine receptors. Since theophylline acts at more than one site, it lacks specificity. In view of the fact that antagonism of the A.sub.1 adenosine receptor, not inhibition of phosphodiesterase, has been shown to result in chloride efflux, such lack of specificity could result in undesired side effects. In addition, large doses of theophylline must be administered to achieve a beneficial effect, at the same time risking side effects from the high toxicity of the compound.
Other compounds that resemble theophylline in basic structure have been tested but have not been found to be useful in the treatment of cystic fibrosis. For example, IBMX (see FIG. 1A), which is structurally similar to theophylline, is nonspecific in activity and highly toxic and, therefore, lacks utility in the treatment of CF. Also ineffective in the activation of chloride efflux are the compounds 2-thio-CPX, KW-3902, and CPT (see FIG. 1B). Similarly, substitution of the propyl group at position R.sub.1 or R.sub.3 of CPX (see FIG. 1A) with a one-carbon group generates a compound that is ineffective in activating chloride efflux from CF cells. Clearly, minor structural differences have a significant, if not substantial, impact on the effectiveness of the compound in the treatment of CF.
A drug of high potency, low toxicity, and high specificity for the A.sub.1 adenosine receptor, however, would be a highly desirable and promising therapeutic agent for the treatment of cells having a reduced apical Cl.sup.- conductance, such as cystic fibrosis cells. Such a drug would not only find utility in the treatment of cystic fibrosis per se but would be therapeutically useful in the treatment of COPD in general.
It is an object of the present invention to provide such a method of treating cells having a reduced apical Cl.sup.- conductance. It is another object of the present invention to provide a method of treating cystic fibrosis cells. It is yet another object of the present invention to provide a method of treating cystic fibrosis cells having a deletion involving phenylalanine at amino acid position 508 of the cystic fibrosis transmembrane regulator.
These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.